5-piperazino-6-hydroxy-5h-benzo-cycloheptenes

ABSTRACT

THE COMPOUNDS ARE 5-AMINO-6-HYDROXY-6,7,8,9-TETRAHYDRO-5H-BENZOCYCLOHEPTENS WHICH ARE USEFUL AS CHEMICAL INTERMEDIATES AND AS CENTRAL NERVOUS SYSTEM STIMULANTS. A COMPOUND DISCLOSED IS 5-ISOPROPYLAMINO-6-HYDROXY-6,7,8,9-TETRAHYDRO-5H-BENZOCYCLOHEPTENE.

United States Patent 3,836,534 S-PIPERAZINO-6-HYDROXY-5H-BENZO-CYCLGHEPTENES Alexander E. Drukker, Milwaukee, and Claude I. Judd,

Mequon, Wis., assignors to Colgate-Palmolive Company, New York, N .Y.

N Drawing. Continuation-impart of abandoned application Ser. No.821,148, May 1, 1969. This application Aug. 16, 1971, Ser. No. 172,193

Int. Cl. (307d 51/70 U.S. Cl. 260-268 BC 2 Claims ABSTRACT OF THEDISCLOSURE The compounds are-amino-6-hydroXy-6,7,8,9-tetrahydro-SH-benzocycloheptenes which areuseful as chemical intermediates and as central nervous systemstimulants. A compound disclosed is5-isopropylamino-6-hydroxy-6,7,8,9-tetrahydro-5H-benzocycloheptene.

RELATED CASE This application is a continuation-in-part of our earlierapplication Ser. No. 821,148, filed May 1, 1969 now abandoned.

DETAILED DESCRIPTION The compounds of the present invention may berepresented by the following formula:

in which X is selected from hydrogen, lower alkoxy of 1 to 4 carbonatoms such as methoxy, ethoxy or propoxy, halo such as chloro, bromo orfluoro and trifluoromethyl, and Am is a group selected from in which Rand R are the same or different groups selected from hydrogen, a loweralkyl of 1 to 4 carbon atoms such as methyl, ethyl or isopropyl, ahydroxylower alkyl such as hydroxymethyl or hydroxyethyl, a lower acylgroup such as acetyl, benzoyl and phenyllower alkyls of 7 to 13 carbonatoms such as benzyl, phenethyl and phenylisopropyl, or

(b) Groups in which represents an amino group such as morpholino,pyrrolidino, piperidino, N-lower alkyl piperazino groups such asN-methyl-piperazino, N-(phenyl-lower alkyl)piperazino groups such asN-benzyl-piperazino and N-(hydroxylower alkyl)piperazino groups such as4-(beta-hydroxyethyl)piperazino.

The novel compounds of the present invention are preferably preparedfrom starting materials which may berepresented by the followingformula:

Patented Sept. 17, 1974 "Ice Representative of the starting materialswhich can be employed are the following:

5,6-epoxy-6,7,8,9rtetrahydro-SH-benzocycloheptene,

2 chloro 5,6-epoxy-'6,7,8,9-tetrahydro-5H-benzocycloheptene, l

3 fluoro 5,6-epoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene,

2 methoxy 5,6-epoxy 6,7,8,9 tetrahydro-SH-benzocycloheptene,

3 trifluoromethyl 5,6 epoxy 6,7,8,9-tetrahydro-5H- benzocycloheptene.

The above 5,6 epoxy 6,7,8,9-tetrahydro-5H-benzocycloheptenes are oldcompounds and may be prepared as described in the literature. (T. A.Crabb et al., Journal of the Chemical Society, 1958, page 4276.)

The compounds of the present invention are preferably prepared byreacting a selected 5,6-epoxy derivate with ammonia or an amine. Thereaction is preferably conducted in an organic solvent such as benzene,at temperatures of to C. in an autoclave.

The process may be illustrated as follows:

Am OH Representative of the amines that may be employed in the reactionare the following:

ammonia,

methylamine,

benzylamine, dimethylamine, methylbenzylamine, piperidine,

4-substitnted piperazine, and morpholine.

Representative of the compounds which may be prepared by the describedprocess are the following:

Those compounds in which. R or R is acyl may be prepared by treating thecorresponding primary or secondary amine derivative with anacylatingagent, such as benzoyl chloride, in the presence of pyridine. Theprocess may be illustrated asfollowst acylehloride X in which X doesinterfere with or partake in the reaction.

Representative of ,the acylating agents which may be employed are thefollowing; 7

acetyl chloride, 7 acetylbromide, propionyl chloride, N-butyrylchloride, and benzoyl Chloride.

Examples of some of the S-acylatnino-6-hydroxy-6,7,8,9-tetrahydro-5H-benzocycloheptenes thus prepared are The compounds ofthe present invention are useful as intermediates in the preparation ofmore complex chemical compounds. For example, the thiocyanic acidaddition salts of the compounds may be condensed with formaldehyde toform resinous materials useful as pickling agents as described in US.Pats. 2,425,320 and 2,606,155. The compounds may also be used in theform of their fluosilicic acid addition salts as mothproofing agents asdescribed in U.S. Pats. 1,915,334 and 2,075,359.

The compounds have also been found to have utility as central nervoussystem stimulants. In mouse behavioral studies the following compoundswere found in 10 mg./ kg. intraperitoneal doses to cause a stimulationof the central nervous system:

(N-methyl-N-Z-hydroxyethyl)amino-6-hydroxy-6,7,8,

9-tetrahydro-SH-benzocycloheptene,

5 (1methyl-4-piperazinyl)-6-hydroxy-6,7,8,9-tetrahydro-SH-benzocycloheptene,

5 amino 6-hydroxy-6,7,8,9-tetrahydro-5I-I-benzocycloheptene,

5 amino 6-hydroxy-6,7,8,9-tetrahydro-SH-benzocycloheptene, and

5 benzoylamino-6-hydroxy-6,7,8,Q-tetrahydro-SH-benzocycloheptene.

When employed as pharmaceutical agents the compounds are preferably usedin the form of acid addition salts. Such acid addition salts may beconveniently prepared by simply contacting the compounds with a suitableacid in a mutual solvent and then removing the solvent to obtain thedesired salt. Examples of acid which may be employed are hydrochloricacid, succinic acid, tartaric acid, benzoic acid or fumaric acid.

Quarternary ammonium salts of the compounds may 'be formed byconventional techniques employing a suitable alkylating agent such asmethyl chloride, methyl iodide or ethyl bromide.

Pharmaceutical dosage forms containing the active ingredients aregenerally prepared by combining the active ingredient or ingredientswith a major amount of one or more suitable pharmaceutical diluents andthen forming the resulting mixture into unit dosage forms suitable fororal or parenteral administration.

The unit dosage forms will generally contain from 5 to 250 mg. of theactive ingredients. One or more of such units may be administered dailydepending upon the patients physical size and the severity of thecondition being treated. However, generally the daily dosage will notexceed 100 mg. of the activeingredient per kilogram of the patient'sbody weight.

The following examples are presented to illustrate the invention:

EXAMPLE 1 a 5- (N-Methyl-N-Z-hydroxyethyl) amino-fiehyd'roxy-6,7,8,9-tetrahydro-SH-benzocycloheptene A mixture of 8- g. (0.05 mole)"of 5,6-epoxy-6,7,8,9- tetrahydro 5H benzocycloheptene and 5.63 g.(0.075 mole) of methylaminoethanol'is heated to 170 for 4.5

hours. The viscous liquid is distilled to yield S-(N-methyl- N2-hydroxyethyl) amino-6-hydroxy,6,7,8,9-tetrahydro-SH-benzocycloheptene, b.p. 180 (0.1 mm.).

Analysis-Calcd. for C I-I NO C, 71.45; H, 9.00; N, 5.95. Found: C,71.82; H, 9.21; N, 5.85.

EXAMPLE 2 S-Dimethylamino-6-hydroxy-6,7,8,9 tetrahydro-5H-benzocycloheptene A solution of 8 g. (0.05 mole) of 5,6-epoxy-6,7,8,9-

tetrahydro-SH-benzocycloheptene in 50 ml. of benzene' containing 5 g.(0.08 mole) of dimethylamine is heated 4 hours in an autoclave at 150.The reaction mixture is concentrated and distilled to yield5-dimethylamino-6- hydroxy 6,7,8,9-tetrahydro-SH-benzocycloheptene, b.p.(0.15 mm.), mp. 68-69".

AnalysisCalcd. for C H NO: C, 76.04; H, 9.30; N, 6.82. Found: C, 76.12;H, 8.85; N, 6.72.

EXAMPLE 3 5 -Isopropylamino-6-hydroxy-6,7,8,9-tetrahydro-SH-benzocycloheptene A solution of 24 g. (0.15 mole) of5,6-epoxy-6,7,8,9- tetrahydro-SH-benzocycloheptene and 11.8 g. (0.2mole) of isopropylamine in ml. of benzene is heated 4 hours in anautoclave at 150, cooled, concentrated, and the residue recrystallizedfrom 100 ml. of hot acetonitrile to give 5isopropylamino-6-hydroxy-6,7,8,9-tetrahydro-5H- benzocycloheptene, m.p.l08113. Furthermore recrystallizations from acetonitrile increases themelting point to 112-115".

Analysis.Calcd. for C H NO: C, 76.66; H, 9.66; N, 6.39. Found: C, 76.65;H, 9.77; N, 6.32.

EXAMPLE 4 5-( l-Methyl-4-piperazinyl -6-hydroxy-6,7,8,9 tetrahydro- 5H-benzocycloheptene EXAMPLE 5 S-Amino-6-hydroxy-6,7,8,9-tetrahydro-SH-benzocycloheptene A mixture of 24 g. (0.15 mole) of5,6-epoxy-6,7,8,9- tetrahydro-SH-benzocycloheptene, 25 g. of sodiumazide, 1 liter of dioxane and 250 ml. of water are stirred and refluxedfor 48 hours under nitrogen. Part of the dioxane is removed bydistillation, the mixture is diluted With water and extracted withether. The ethereal extracts are Washed with Water, dried over potassiumcarbonate, filtered, and concentrated to yield the crude azide carbinolin the form of a yellow brown oil. Part of this (10.15 g.) is dissolvedin 225 ml. of ethanol, some gray precipitate is filtered off, and to thefiltrate is added 100 mg. of platinum oxide. The solution ishydrogenated for 2 hours at room temperature and 60 lbs. pressure, thecatalyst is removed by filtration and the filtrate concentrated. Theresidue is redissolved in warm benzene, washed with Water, dried shortlyover sodium sulfate, filtered and concentrated. The residue isrecrystallized from 100 ml. of hot ethanol to yield5-arnino-6-hydroxy-6,7,8,9-tetrahydro-SH-benzocycloheptene, mp. 161162.

Analysis.Calcd. for C -H NO: C, 74.54; H, 8.53; N, 7.90. Found: C,74.18; H, 8.62; N, 7.79.

5 EXAMPLE 6 To a slurry of 14 g. (0.079 mole) of5-amino-6-hydroxy-6,7,8,9-tetrahydro-SH-benzocycloheptene in 300 ml. ofpyridine is added dropwise 11.9 g. (0.085 mole) of benzoyl chloride. Themixture is stirred 1 hour at room temperature, quenched in water,filtered off, and recrystallized from methanol to yield5-benzoylamino-6-hydroxy 6,7,8,9 tetrahydro 5H benzocycloheptene, m.p.217.

Analysis.Calcd. for C H NO C, 76.84; H, 6.81; N, 4.98. Found: C, 76.72;H, 7.03; N, 4.97.

We claim:

1. The compound 5 (1 methyl 4piperazinyl)-6-hydroxy-6,7,8,9-tetrahydro-SH-benzocyclohefitene andpharmaceutically acceptable acid addition salts thereof.

2. The compound of claim 1 which is 5-(1-methy1-4-piperazinyl)-6-hydroxy-6,7,8,9 tetrahydro 5H benzocycloheptene.

References Cited UNITED STATES PATENTS 2,700,686 1/1955 Dickey et a1260-633 3,458,577 7/1969 Galantay 260571 3,651,143 3/1972 Galantay260268 BC OTHER REFERENCES Khanna et a1, Indian Jour. Chcm., vol. 6, pp.6-10 (1968).

Khanna et al., Chem. Abstr., vol. 68, la. 87060v (1968).

15 DONALD G. DAVIS, Primary Examiner U.S. C1. X.R.

